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ABSTRACT: Embryonic stem (ES) cells and trophoblast stem (TS) cells are both derived from early embryos, yet these cells have distinct differentiation properties. ES cells can differentiate into all three germ layer cell types, whereas TS cells can only differentiate into placental cells. It has not been determined whether TS cells can be converted into ES-like pluripotent stem (PS) cells. Here we report that overexpression of a single transcription factor, Oct4, in TS cells is sufficient to convert TS cells into a pluripotent state. These Oct4 induced pluripotent stem (OiPS) cells have the epigenetic characteristics of ES cells, including X chromosome reactivation and elevated H3K27 me3 modifications. The gene expression profile of OiPS cells and ES cells was very similar. Moreover, OiPS cells can differentiate into the three germ layer cell types in vitro and in vivo. More importantly, chimeric mice with germline transmission could be efficiently produced from OiPS cells. To our knowledge, this is the first evidence showing that only one single transcription factor could convert the non-embryonic TS cells into pluripotent stem cells with pluripotency. Overall design: Gene expression profile of iPS cells and trophoblast stem cells were generated by Affymetrix Mouse Gene 1.0 ST Array. The Gene expression profile of ES cell R1 in GSE17004 was used as control. Three biological repeats were included for each line.

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Project description:Embryonic stem (ES) cells and trophoblast stem (TS) cells are both derived from early embryos, yet these cells have distinct differentiation properties. ES cells can differentiate into all three germ layer cell types, whereas TS cells can only differentiate into placental cells. It has not been determined whether TS cells can be converted into ES-like pluripotent stem (PS) cells. Here we report that overexpression of a single transcription factor, Oct4, in TS cells is sufficient to convert TS cells into a pluripotent state. These Oct4 induced pluripotent stem (OiPS) cells have the epigenetic characteristics of ES cells, including X chromosome reactivation and elevated H3K27 me3 modifications. The gene expression profile of OiPS cells and ES cells was very similar. Moreover, OiPS cells can differentiate into the three germ layer cell types in vitro and in vivo. More importantly, chimeric mice with germline transmission could be efficiently produced from OiPS cells. To our knowledge, this is the first evidence showing that only one single transcription factor could convert the non-embryonic TS cells into pluripotent stem cells with pluripotency. Gene expression profile of iPS cells and trophoblast stem cells were generated by Affymetrix Mouse Gene 1.0 ST Array. The Gene expression profile of ES cell R1 in GSE17004 was used as control. Three biological repeats were included for each line.

Project description:Esrrb is a transcription factor implicated in embryonic stem (ES) cell self-renewal, yet its knockout causes intrauterine lethality due to defects in trophoblast development. Here we show that in trophoblast stem (TS) cells, Esrrb is a downstream target of fibroblast growth factor (Fgf) signalling and is critical to drive TS cell self-renewal. In contrast to its occupancy of pluripotency-associated loci in ES cells, Esrrb sustains the stemness of TS cells by direct binding and regulation of TS cell-specific transcription factors including Elf5 and Eomes. To elucidate the mechanisms whereby Esrrb controls the expression of its targets, we characterized its TS cell-specific interactome by mass spectrometry. Unlike in ES cells, Esrrb interacts in TS cells with the histone demethylase Lsd1 and with the RNA Polymerase II-associated Integrator complex. Our findings provide new insights into both, the general and context-dependent wiring of transcription factor networks in stem cells by master transcription factors.

Project description:Chavez2009 - a core regulatory network of OCT4 in human embryonic stem cells
A core OCT4-regulated network has been identified as a test case, to analyase stem cell characteristics and cellular differentiation.
This model is described in the article:
In silico identification of a core regulatory network of OCT4 in human embryonic stem cells using an integrated approach.
Chavez L, Bais AS, Vingron M, Lehrach H, Adjaye J, Herwig R
BMC Genomics, 2009, 10:314
Abstract:
BACKGROUND: The transcription factor OCT4 is highly expressed in pluripotent embryonic stem cells which are derived from the inner cell mass of mammalian blastocysts. Pluripotency and self renewal are controlled by a transcription regulatory network governed by the transcription factors OCT4, SOX2 and NANOG. Recent studies on reprogramming somatic cells to induced pluripotent stem cells highlight OCT4 as a key regulator of pluripotency.
RESULTS: We have carried out an integrated analysis of high-throughput data (ChIP-on-chip and RNAi experiments along with promoter sequence analysis of putative target genes) and identified a core OCT4 regulatory network in human embryonic stem cells consisting of 33 target genes. Enrichment analysis with these target genes revealed that this integrative analysis increases the functional information content by factors of 1.3 - 4.7 compared to the individual studies. In order to identify potential regulatory co-factors of OCT4, we performed a de novo motif analysis. In addition to known validated OCT4 motifs we obtained binding sites similar to motifs recognized by further regulators of pluripotency and development; e.g. the heterodimer of the transcription factors C-MYC and MAX, a prerequisite for C-MYC transcriptional activity that leads to cell growth and proliferation.
CONCLUSION: Our analysis shows how heterogeneous functional information can be integrated in order to reconstruct gene regulatory networks. As a test case we identified a core OCT4-regulated network that is important for the analysis of stem cell characteristics and cellular differentiation. Functional information is largely enriched using different experimental results. The de novo motif discovery identified well-known regulators closely connected to the OCT4 network as well as potential new regulators of pluripotency and differentiation. These results provide the basis for further targeted functional studies.
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Project description:In the murine system, Oct4, Sox2, c-Myc and Klf4 are sufficient to convert fibroblasts to induced pluripotent stem (iPS) cells that exhibit many characteristics of embryonic stem (ES) cells. Herein, we show that the orphan nuclear receptor Esrrb works in conjunction with Oct4 and Sox2 to mediate reprogramming of mouse embryonic fibroblasts (MEFs) to iPS cells. Esrrb reprogrammed cells share similar expression and epigenetic signatures as ES cells. These cells are also pluripotent and can differentiate in vitro and in vivo into the three major embryonic cell lineages. Furthermore, these cells contribute to mouse chimeras and are germline transmissible. In ES cells, Esrrb targets many genes involved in selfrenewal and pluripotency. This suggests that Esrrb may mediate reprogramming through the up-regulation of ES cell-specific genes. Our findings also indicate that it is possible to reprogram MEFs without exogenous Klf transcription factors and link a nuclear receptor to somatic cell reprogramming. This SuperSeries is composed of the SubSeries listed below. Overall design: Refer to individual Series

Project description:In the murine system, Oct4, Sox2, c-Myc and Klf4 are sufficient to convert fibroblasts to induced pluripotent stem (iPS) cells that exhibit many characteristics of embryonic stem (ES) cells. Herein, we show that the orphan nuclear receptor Esrrb works in conjunction with Oct4 and Sox2 to mediate reprogramming of mouse embryonic fibroblasts (MEFs) to iPS cells. Esrrb reprogrammed cells share similar expression and epigenetic signatures as ES cells. These cells are also pluripotent and can differentiate in vitro and in vivo into the three major embryonic cell lineages. Furthermore, these cells contribute to mouse chimeras and are germline transmissible. In ES cells, Esrrb targets many genes involved in selfrenewal and pluripotency. This suggests that Esrrb may mediate reprogramming through the up-regulation of ES cell-specific genes. Our findings also indicate that it is possible to reprogram MEFs without exogenous Klf transcription factors and link a nuclear receptor to somatic cell reprogramming. We used microarrays to detail the global programme of gene expression of ES cells, Esrrb reprogrammed iPS cell lines and MEFs. Keywords: comparative Overall design: Two biological replicates for ES cells, each iPS cell line and each type of MEF. The global gene expression profiles of the Esrrb reprogrammed iPS cell lines were compared to ES cells and MEFs.

Project description:Reprogramming of ES cells towards the trophoblast lineage, and specifally into self-renewing TS cells, can seemingly be achieved by manipulation of transcription factors such as Cdx2 and Oct4, or modulation of signalling cascades, notably Ras signalling. Here we analyze the arising cells from such treatment in detail for the efficiency and completeness of the reprogramming process. We find that the reprogrammed cells retain an epigenetic and transcriptional memory of their ES cell origin and are not equal to bona fide trophectoderm-derived TS cells. DNA methylation analysis in conventional ES and TS cells and various ES-to-TS reprogramming models

Project description:Reprogramming of ES cells towards the trophoblast lineage, and specifally into self-renewing TS cells, can seemingly be achieved by manipulation of transcription factors such as Cdx2 and Oct4, or modulation of signalling cascades, notably Ras signalling. Here we analyze the arising cells from such treatment in detail for the efficiency and completeness of the reprogramming process. We find that the reprogrammed cells retain an epigenetic and transcriptional memory of their ES cell origin and are not equal to bona fide trophectoderm-derived TS cells. RNA-seq expression analysis in conventional ES and TS cells and various ES-to-TS reprogramming models

Project description:In the murine system, Oct4, Sox2, c-Myc and Klf4 are sufficient to convert fibroblasts to induced pluripotent stem (iPS) cells that exhibit many characteristics of embryonic stem (ES) cells. Herein, we show that the orphan nuclear receptor Esrrb works in conjunction with Oct4 and Sox2 to mediate reprogramming of mouse embryonic fibroblasts (MEFs) to iPS cells. Esrrb reprogrammed cells share similar expression and epigenetic signatures as ES cells. These cells are also pluripotent and can differentiate in vitro and in vivo into the three major embryonic cell lineages. Furthermore, these cells contribute to mouse chimeras and are germline transmissible. In ES cells, Esrrb targets many genes involved in selfrenewal and pluripotency. This suggests that Esrrb may mediate reprogramming through the up-regulation of ES cell-specific genes. Our findings also indicate that it is possible to reprogram MEFs without exogenous Klf transcription factors and link a nuclear receptor to somatic cell reprogramming. Global gene expression effects of silencing the Esrrb gene. We used microarrays to detail the global programme of gene expression after silencing the Esrrb gene. Keywords: time-course Three biological replicates each for control GFP and Esrrb RNAi. The global gene expression profiles of the Esrrb knockdown cells were compared to control GFP knockdown cells for days 2, 4 and 6.